JP3770518B2 - Oral drugs concealing bitterness - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to an oral pharmaceutical composition that masks an unpleasant taste.
[0002]
[Prior art]
Many techniques have been developed for masking drugs with an unpleasant taste. For example, a method of coating a granule with a water-soluble film (JP-A-4-28212), melting a wax having a melting point of 40 to 100 ° C., and dispersing and solidifying a drug exhibiting an unpleasant flavor therein A method for obtaining a powder or the like (Japanese Patent Laid-Open No. 7-267850) is known. On the other hand, in the case of a liquid preparation, it is known to use an oral liquid preparation such as syrup in order to enhance the feeling of administration, and it is widely used as a dosage form suitable for children, the elderly and the like. A syrup is a sweet dosage form, but if the drug to be dissolved has an unpleasant taste, it cannot be concealed simply by sweetness and is difficult to take, and compliance is also reduced. Furthermore, in JP-A-4-346937, as a method for reducing bitterness, a gelling agent selected from agar, gelatin or κ-carrageenan and a seasoning agent are added to a bitter substance to form a seasoning jelly. A characteristic bitterness reduction method is disclosed. This method reduces the contact of the bitter substance with the tongue by making it into a jelly form, and the bitter substance that partially dissolves masks the bitter taste with a seasoning agent.
[0003]
[Problems to be solved by the invention]
Many technologies such as those described above have been studied for the purpose of masking drugs with an unpleasant taste, but the manufacturing process is complicated, the effect is insufficient, and there are quality problems. However, there is still nothing to be satisfied and further technology is required.
[0004]
[Means for Solving the Problems]
The present invention is an oral pharmaceutical composition that conceals an unpleasant taste containing a basic drug having an unpleasant taste and an anionic polymer substance. In addition, the present invention is a method for concealing an unpleasant taste characterized by blending an anionic polymer substance with a basic drug having an unpleasant taste. Furthermore, the present invention is a masking agent for a basic drug having an unpleasant taste made of an anionic polymer substance.
[0005]
In the present invention, the basic drug means that the educt is basic, and is not necessarily basic when a salt is formed. The basic drug in the present invention is not particularly limited, and among drugs taken orally such as antibiotics, anti-dementia drugs, antiplatelet drugs, antidepressants, cerebral circulation metabolism improving drugs or antiallergic drugs, bitterness, Any basic drug having an unpleasant taste such as irritation can be used. Specifically, for example, ticlopidine hydrochloride, maprotiline hydrochloride, ifenprodil hydrochloride, berberine chloride, digitoxin, sulpyrine, azelastine hydrochloride, ethylephrine hydrochloride, diltiazem hydrochloride, propranolol hydrochloride , Chloramphenicol, aminophylline, erythromycin, phenobarbital, calcium pantothenate, indeloxazine hydrochloride, aminoguanidine hydrochloride, donepezil hydrochloride, (RS) -1- (isopropoxycarbonyloxy) ethyl (+)-(6R, 7R ) -7 {(z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoa Toamide} -3-N, N-dimethylcarbamoyloxymethyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate hydrochloride, cefcapene hydrochloride, etc. it can. Among them, donepezil hydrochloride, (RS) -1- (isopropoxycarbonyloxy) ethyl (+)-(6R, 7R) -7 {(z) -2- (2-aminothiazol-4-yl) -2-hydroxyimino Acetamide} -3-N, N-dimethylcarbamoyloxymethyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate hydrochloride Play. Donepezil hydrochloride is the chemical name (1-benzyl-4- (5,6-dimethoxyindanone-2-yl) methylpiperidine hydrochloride, which is a mild to moderate Alzheimer's therapeutic agent, but its aqueous solution has an intense bitter taste, (RS) -1- (isopropoxycarbonyloxy) ethyl (+)-(6R, 7R) -7 {(z) -2- (2-aminothiazole-4 -yl) -2-Hydroxyiminoacetamide} -3-N, N-dimethylcarbamoyloxymethyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate hydrochloride Is an effective antibiotic even when administered orally, but has a strong bitter taste.
[0006]
The anionic polymer substance in the present invention is not particularly limited, but acidic polysaccharides are preferable, and specific examples include carrageenan, chondroitin sulfate, dextran sulfate, alginic acid, gellan gum and xanthan gum and salts thereof. As carrageenan, ι, κ, λ, and the like are known, and any of them can be used. However, in the case of a liquid or jelly agent, κ-carrageenan and ι-carrageenan are preferable, and dextran sulfate is also preferable. In the case of a solid agent, κ-carrageenan, sodium chondroitin sulfate and sodium alginate are particularly preferable. A commercially available carrageenan or the like can be used, and can be obtained from FMC Corporation (USA), Systems Bio Industries Co., Ltd, and the like.
[0007]
The dosage form of the oral pharmaceutical composition in the present invention means a dosage form to be taken orally as a solid, liquid or jelly, and specific examples of the solid include granules, fine granules, powders, tablets. , Pills, etc., and examples of liquids include syrups, elixirs, emulsions, suspensions, etc., especially granules, fine granules, powders, syrups, jellys The case is preferred. These dosage forms are listed in the Japanese Pharmacopoeia except for jelly.
[0008]
The administration method of the oral pharmaceutical composition according to the present invention is not particularly limited, and can be administered orally once to several times a day before, after, or between meals depending on the nature of the drug.
[0009]
The amount of the drug in the solid drug varies depending on the nature of the drug and cannot be generally specified, but is generally 0.1 to 1000 mg after a single dose. The concentration of the drug in the oral solution that masks the unpleasant taste is generally 0.1 to 500 mg / ml, preferably 0.5 to 100 mg / ml. When the drug is donepezil hydrochloride, the concentration is preferably 0.5 to 5 mg / ml. In the present invention, the ratio of the basic drug to the anionic polymer substance is generally 0.1 to 20 parts by weight, preferably 0.5 to 10 parts by weight, based on 1 part by weight of the basic drug. is there. When the oral pharmaceutical composition according to the present invention is a solid preparation, an unpleasant taste masking effect can be obtained by uniformly mixing the drug and the anionic polymer substance. Also by mixing drugs and excipients, separately dissolving an anionic polymer in a solvent such as water, mixing with other binders as necessary, adding gradually and granulating, An unpleasant taste masking effect is obtained. Depending on the type of drug, granulation increases the effect of hiding unpleasant taste. In any case, in the present invention, the anionic polymer substance functions as a substance that masks an unpleasant taste such as a bitter taste of a basic drug.
[0010]
The manufacturing method of the oral pharmaceutical composition which concealed the unpleasant taste based on this invention is not specifically limited, It can be based on the method generally used. For example, in the case of a granule, an excipient such as lactose, mannitol, starch and crystalline cellulose, a disintegrant such as carboxymethylcellulose, etc. are further mixed with a drug, κ-carrageenan, and a binder such as hydroxypropylcellulose is dissolved. While adding the solution, it can be produced with a commonly used granulator. Moreover, the manufacturing method of an oral liquid preparation is not specifically limited, For example, a basic drug and an anionic polymer substance can be melt | dissolved and manufactured in water. Furthermore, sweeteners such as sucrose, xylitol, mannitol, glucose, aspartame, saccharin, and flavoring agents such as vanilla essence and apple flavor can be added.
[0011]
【The invention's effect】
The oral pharmaceutical composition according to the present invention has a bitter taste, numbness, astringency and other unpleasant tastes peculiar to the drug concealed, so it is very easy to take and improves patient compliance. It is particularly useful for infants and elderly people. The mechanism by which the oral preparation according to the present invention masks an unpleasant taste is considered as follows. That is, a basic drug having an unpleasant taste interacts with acidic polysaccharides and reduces the binding rate of the tongue to the bitter taste receptor when dissolved in saliva or by reducing free substances in solution. At the same time, it is thought to reduce the occurrence of numbness.
[0012]
Test example 1
A 2 mg / ml aqueous solution of donepezil hydrochloride was prepared, and 50 mg of κ-carrageenan, chondroitin sulfate or dextran sulfate was dissolved in 5 ml thereof, and 2 subjects (indicated by A and B in the table) contained the entire amount in their mouths, The degree of numbness was evaluated in five levels. The results are shown in Table 1. As is apparent from Table 1, the bitter taste of donepezil hydrochloride was significantly suppressed by the addition of κ-carrageenan and the like.
[0013]
Table 1 Evaluation criteria ────────────────────────────────────
Bitterness I don't feel anything I feel something A little bitter Bitter Very bitter ─────────────────────────────────────
Numbness Nothing Feeling Something Numbness Numbness Very Numbness ─────────────────────────────────────
− ± ++ ++ ++
────────────────────────────────────
Results ────────────────────────────────────
Sample / Subject A B
Bitter numbness bitterness numbness ────────────────────────────────────
Donepezil hydrochloride (D) +++ +++ +++ +++
────────────────────────────────────
D + kappa carrageenan + ± + +
────────────────────────────────────
D + chondroitin sulfate ++++++++++
────────────────────────────────────
D + dextran sulfate + ± + +
────────────────────────────────────
[0014]
Test example 2
Using ticlopidine hydrochloride (20 mg / ml), maprotiline hydrochloride (5 mg / ml) and ifenprodil tartrate (4 mg / ml), the carrageenan's bitterness and numbness concealing effect were examined. Test methods and evaluation criteria were the same as in Test Example 1. The results are shown in Table 2.
[0015]
────────────────────────────────────
Sample / Subject A B
Bitter numbness bitterness numbness ────────────────────────────────────
Ticlopidine hydrochloride +++ +++ +++ +++
────────────────────────────────────
Ticlopidine hydrochloride + kappa carrageenan (1mg / ml) ± ++ ± ++
+ Λ Carrageenan (1mg / ml)
────────────────────────────────────
Ticlopidine hydrochloride + kappa carrageenan (2mg / ml) − + − ±
────────────────────────────────────
Maprotiline hydrochloride ++ ++
────────────────────────────────────
Maprotiline hydrochloride + kappa carrageenan (2mg / ml) − − − −
────────────────────────────────────
Ifenprodil tartrate +-++-
────────────────────────────────────
Ifenprodil tartrate + kappa carrageenan (2mg / ml) ± − − −
────────────────────────────────────
[0016]
As is clear from Table 2, the bitterness and numbness of each drug were remarkably suppressed by the addition of carrageenan. In particular, the taste of ticlopidine hydrochloride is extremely bitter and irritating, but being significantly suppressed by the addition of carrageenan indicates that the effect of the present invention is extremely excellent.
[0017]
Test example 3
(RS) -1- (Isopropoxycarbonyloxy) ethyl (+)-(6R, 7R) -7 {(z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide} -3 -N, N-dimethylcarbamoyloxymethyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate hydrochloride (denoted as compound A in Table 3) with alginic acid Sodium, chondroitin sulfate sodium, κ-carrageenan, ι-carrageenan, mannitol, corn starch, copolyvidone and the like were blended in the amounts shown in Table 3, and granules were produced by the method according to Example 3. The test was conducted by 3 subjects including 0.5 g of each test granule in the mouth, and the evaluation was made according to the following seven evaluation criteria.
+4: Strongly bitter, unable to take, +3: Very bitter, +2: Bitter, +1: Slightly bitter, 0: Neither bitter, -1: No bitterness, -2: Somewhat delicious Are shown in Table 3. From Table 3, it is clear that the granules containing the anionic polymer substance according to the present invention remarkably suppress bitterness.
[0018]
Table 3
───────────────────────────────────────
Ingredient Prescription (%) Evaluator A Evaluator B Evaluator C
───────────────────────────────────────
Compound A 15 +4 +3 +4
Mannitol 85
───────────────────────────────────────
Compound A 15 +1 0 → + 2 +1
Sodium alginate 15 Note 1
Mannitol 70
───────────────────────────────────────
Compound A 15 0 0 0
Chondroitin sulfate Na 15
Mannitol 70
───────────────────────────────────────
Compound A 15 0 0 0
κ Carrageenan 15
Cornstarch 30
Mannitol 40
───────────────────────────────────────
Compound A 15 −1 0 → + 1 0
κ & ι Carrageenan 15 Note 1
Copolividone 15
Mannitol 55
───────────────────────────────────────
Compound A 15 0 -1 0
κ Carrageenan 14.5
λ Carrageenan (with solvent) 0.5
Cornstarch 30
Mannitol 40
───────────────────────────────────────
Compound A 14.5 -2 -2 -2
κ Carrageenan 14.5
Alginate Na (with solvent) 2
Cornstarch 30
Mannitol 32.5
Aerosil 4
Strawberry essence 0.5
Red No. 102 Trace Aspartame 2
───────────────────────────────────────
Note 1: Bitter later when taken with water [0019]
Test example 4
According to the method shown in Table 4, ticlopidine hydrochloride, κ-carrageenan, corn starch, mannitol and hydroxypropylcellulose (indicated as HPC-L in Table 4) are mixed thoroughly, and granulated by adding water to obtain granules. It was. Two subjects (indicated as A and B in Table 4) contained 0.5 g of this granule in their mouths, and the taste was determined. Evaluation criteria were in accordance with Test Example 1. The results are shown in Table 4.
[0020]
Table 4
───┬───────────────────────────────────
│ Control Formula 1 Formula 2 Formula 3
───┼───────────────────────────────────
│Ticlopidine 100 100 100 100
│κ Carrageenan 0 100 200 300
│Mannitol 670 570 470 370
│Corn Starch 200 200 200 200
│HPC-L 30 30 30 30
├───────────────────────────────────
│ Total 1000 1000 1000 1000
───┼─┬─────────────────────────────────
│ │Bitterness + ± − −
│A├─────────────────────────────────
│ │ Numbness ++++ ++++
├─┼─────────────────────────────────
Fruit │ │ Bitterness + + − −
│B├─────────────────────────────────
│ │ Numbness ++++ ++++ −
───┴─┴─────────────────────────────────
mg / granule 1g
[0021]
From Table 4, it is clear that the present invention can conceal the very unpleasant taste of ticlopidine even in the solid state. From the test examples shown above, the remarkable effect of the present invention is clear.
[0022]
【Example】
The present invention will be described in more detail with reference to examples below, but the present invention is not limited to these examples.
[0023]
Example 1
(RS) -1- (Isopropoxycarbonyloxy) ethyl (+)-(6R, 7R) -7 {(z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide} -3 -N, N-dimethylcarbamoyloxymethyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate hydrochloride 15 g, κ-carrageenan 15 g, corn starch 30 g and mannitol 40 g Were mixed using a rolling granulator, about 20 ml of water was gradually added and kneaded, and dried through a 32 mesh sieve to produce granules.
[0024]
Example 2
15 g of the drug used in Example 1, 15 g of sodium chondroitin sulfate, and 70 g of mannitol are mixed using a tumbling granulator, about 20 ml of water is gradually added and kneaded, passed through a 32 mesh sieve, dried and granulated An agent was obtained.
[0025]
Example 3
15 g of the drug used in Example 1, 15 g of carrageenan (a mixture of ι and κ), 15 g of copolyvidone and 55 g of mannitol were mixed using a tumbling granulator, and approximately 15 ml of water was gradually added and kneaded. It was dried through a mesh sieve to obtain granules.
[0026]
Example 4
58 g of the drug used in Example 1, 58 g of κ-carrageenan, 120 g of corn starch, 130 g of mannitol and 16 g of Aerosil were mixed, and 8 g of sodium alginate dissolved in 392 ml of water and a trace amount of edible red No. 102 were sprayed using a fluid bed granulator. And then dried. Next, 2 g of strawberry essence was sprayed and dried, and then 8 g of aspartame was mixed to produce a fine granule.
[0027]
Example 5
15 g of the drug used in Example 1, 14.5 g of κ-carrageenan, 30 g of corn starch and 40 g of mannitol were mixed, and 0.5 g of λ-carrageenan dissolved in 25 ml of water was sprayed using a fluid bed granulator to obtain a fine granule. Manufactured.
[0028]
Example 6
Mix 10g cefcapene pivoxil hydrochloride, 10g κ-carrageenan, 30g corn starch, 48g mannitol and 2g aspartame using a tumbling granulator, gradually add 20ml of water, knead, granulate through 32 mesh sieve An agent was produced.

Claims (5)

Oral being a granule, fine granule, powder, tablet or pill containing (1) a basic drug having an unpleasant taste, and (2) an anionic polymer selected from carrageenan, dextran sulfate and salts thereof Pharmaceutical composition. The oral pharmaceutical composition according to claim 1, wherein the basic drug having an unpleasant taste is an antibiotic, an anti-dementia drug, an antiplatelet drug, an antidepressant, a cerebral circulation metabolism improving drug or an antiallergic drug. A basic drug with an unpleasant taste is donepezil hydrochloride, (RS) -1- (isopropoxycarbonyloxy) ethyl (+)-(6R, 7R) -7 {(z) -2- (2-aminothiazole- 4-yl) -2-hydroxyiminoacetamide} -3-N, N-dimethylcarbamoyloxymethyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate hydrochloride The oral pharmaceutical composition according to claim 1 or 2, which is a salt, ticlopidine hydrochloride, maprotiline hydrochloride, ifenprodil tartrate or cefcapene pivoxil hydrochloride. The oral drug according to claim 1, 2, or 3, comprising 0.1 to 20 parts by weight of an anionic polymer substance with respect to 1 part by weight of a basic drug having an unpleasant taste. The oral pharmaceutical composition according to any one of claims 1 to 4, wherein an anionic polymer substance selected from carrageenan, dextran sulfate and salts thereof is blended with a basic drug having an unpleasant taste. How to hide unpleasant tastes.